Preclinical Models Unit

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The Preclinical Model Unit is concerned with the design and implementation of preclinical efficacy and safety studies for new drug candidates under GLP or GLP-analogous conditions. This includes the development, establishment and validation of in-vitro and in-vivo models for inflammatory and tumorigenic diseases. The main focus of research is on the development and optimization of humanized mouse models for developing and testing patient-specific therapies.

Plant extracts as active agents for the treatment of chronic inflammatory bowel diseases

Inflammatory bowel diseases (IBD), such as Crohn’s disease and Ulcerative Colitis, are multifactorial disorders of the gastrointestinal tract. The incidence and prevalence of these diseases have been rising constantly in industrial and newly industrialized countries for several decades. Although the diseases show a low mortality rate, patients suffer lifelong from episodes of severe pain and bloody diarrhea. The etiology of IBD is unknown but is assumed to be a combination of genetic predisposition, environmental factors and a dysregulated immune response to the gut microbiota. Hence, current therapies mainly focus on inhibiting the chronic immune response in the gut using immunosuppressive drugs and biologics. Since these therapies are often associated with strong side effects, pharmaceutical companies are pursuing the development of new IBD therapies with less side effects. The model often used for such developments - the acute dextran sulfate sodium (DSS)-induced colitis - cannot adequately represent the chronic course of the diseases. Therefore, the Preclinical Models Unit has developed a chronic model that better represents the course of disease and reduces animal burden. Due to its high reproducibility, the model is very well suited for the preclinical evaluation of therapeutic agents. The model of chronic DSS colitis has already been successfully applied in several industrial projects. Moreover, the therapeutic effect of a plant extract based on sage and bitter apple could be demonstrated in the frame of an internal research project. As a next step, the active components of the extract will be identified and tested for their therapeutic efficacy. The use of phytopharmaceuticals could result in a reduction of the dosis and hence the side effects of classical therapeutics. Furthermore, such therapies could be used in phases of remission and thereby prevent the development of resistance to classical therapeutics. The goal is to make the lifelong therapy needed by IBD patients as effective and tolerable as possible and thus improve the quality of life for these patients.

Development and production of human monoclonal antibodies in a humanized mouse model

This project focuses on developing and producing new kinds of fully humanized monoclonal antibodies for the treatment of tumour diseases (pilot project: triple-negative breast cancer). The development and production of such antibodies can be divided into several steps: The first step entails establishing a humanized mouse model which can be used to generate human monoclonal antibodies against known and yet unknown tumour antigens. A variety of immunization strategies have been created for this purpose in immune-deficient NSG or BRGS mice, which have developed a humanized immune system after the transfusion of human haematopoietic stem cells from cord blood. Tumour-specific human monoclonal antibodies are generated by fusing tumour-specific human B cells from these humanized mice with human plasmocytoma cells, and selected using suitable strategies. Selected candidates are finally tested in an established tumour mouse model in preclinical studies and modified if required (e.g. antibody-drug conjugates), in order to continue improving therapeutic efficacy.

Project manager Claudia Müller

Preclinical animal models for the development of new IBD therapies

Inflammatory bowel diseases (IBDs) are multifactorial diseases of the gastrointestinal tract, the incidence and prevalence of which have been rising constantly in industrial and newly industrialized countries. The etiology of IBD is unknown but is thought to be a combination of genetic predisposition, environmental factors and a dysregulated immune response to the gut microbiota. Current therapeutic approaches, such as immunosuppressives and biologics, often show severe side effects. Thus, there is an urgent need for the development of new therapies based on improved knowledge of the etiological factors of IBDs.

The goal of the in-house research project is to develop and characterize different IBD animal models for testing new therapies and elucidating mechanisms of pathogenesis. Thus, a model of chronic DSS colitis was established which shows typical symptoms such as weight loss and chronic bloody diarrhea. Moreover, the colon tissue of the animals features a continuous immune reaction with resulting ulcerations. In addition, the bacteria-induced chronic colitis has been established as an alternative animal model for IBDs which mainly focuses on the role of the microbiota in disease pathogenesis and / or as a target for novel treatment strategies. Both models can be used for preclinical studies as well as elucidating IBD pathogenesis and developing new therapies. In the latter case, the focus is currently on evaluating the therapeutic potential of phytochemicals.

We are also performing a functional analysis of the gut microbiota in the chronic DSS colitis model using BALB/c mice, together with the Helmholtz Centre for Environmental Research UFZ. The goal of this project is to better understand the interactions of the microbiota and the mucosal immune system in IBDs.

Project managerDr. Ulla Slanina

Immunomodulatory role of the arylhydrocarbon receptor (AhR)

Within the frame of this project, the immunomodulatory effect of the polycyclic aromatic hydrocarbon benzo[a]pyrene (BaP) was characterized in collaboration with the Federal Institute for Risk Assessment (BfR). While the carcinogenic effect of BaP has been known for decades, little attention has been paid so far to the immunomodulatory effect of BaP, particularly of concentrations classified as uncritical. The immunomodulatory effects as well as the decomposition of BaP are mainly regulated by its binding to the arylhydrocarbon receptor (AhR) with subsequent receptor activation. A murine salmonella infection model is used to investigate the impact of BaP on an ongoing immune response. The analysis of the underlying mechanisms is carried out using suitable in-vitro models. Previous investigations have mainly been restricted to the maturation and functional activation of murine macrophages. By using AhR-deficient mice or cells from these animals, the AhR dependence of the observed effects could be demonstrated. Interestingly, the initial findings in our model showed an AhR-dependent immunomodulatory effect of BaP which had a positive impact on the course of disease. In further experiments, selected non-toxic AhR ligands are being analyzed for their therapeutic potential in different disease models.

Project managerSina Riemschneider

Completed projects

Study of the therapeutic efficacy of a transglutaminase inhibitor in an acute DSS colitis model

Study of the therapeutic efficacy of an ion-based immunomodulator in a chronic DSS colitis model

Development of a small animal model and in-vivo studies for evaluating the vitality of human cryopreserved adipose tissue transplants using modern imaging techniques

Analyzing the mechanisms of action and identifying clinically relevant effects of colocynth and sage-based phytopharmaceuticals